The differentiation of stem cells into distinct tissues can be regulated by specific extracellular signaling molecules. For example, Wnt ligands and VEGF differentially regulate mesenchymal stem cell (MSC) fate into adipocytes or osteoblasts (Krishnan et al., 2006, J. Clin. Invest., 116: 1202-1209; Leck-Czernik et al., 2002, Endocrinology, 143: 2376-2384; Liu et al., 2012, J. Clin. Invest., 122: 3101-3113; Prockop et al., 2012, N. Engl. J. Med., 367: 2353-2354). Two human diseases affecting adipocytes and osteoblasts, obesity and osteogenesis imperfecta (OI) type VI, have been associated with an excess or complete absence of pigment epithelium-derived factor (PEDF) (Becker et al., 2011, Am. J. Hum. Genet., 88: 362-371; Homan et al., 2011, J. Bone Miner. Res., 26: 2798-2803; Wang et al., 2008, Eur. J. Endocrinol. 159: 713-718; Bohm et al., 2012, PLoS One, 7:e34035). PEDF is a 50-kDa secreted multifunctional protein of the SERPIN superfamily that has been implicated in the regulation of stem cell populations (Ramirez-Castillejo et al., 2006, Nat Neurosci, 9: 331-339; Doyon et al., 2009, J Biol Chem., 284: 25220-25229; Gonzalez et al., 2010, Proc Natl Acad Sci USA, 107:3552-3557; Kang et al., 2009, Stem Cells Dev, 18:77-91).
The clinical manifestations of high PEDF versus its absence point to its role in adipocyte and osteoblast development. Increased PEDF levels correlate with adiposity in patients with the metabolic syndrome (Wang et al., 2008, Eur. J. Endocrinol. 159: 713-718; Bohm et al., 2012, PLoS One, 7:e34035; Sabater et al., 2010, J Clin Endocrinol Metab, 95: 4720-4728). Here, elevated PEDF likely represents a compensatory measure since PEDF impedes adipogenesis of 3T3-L1 adipocyte precursors and its absence in mice results in ectopic lipid accumulation in organs such as the liver and pancreas (Wang et al., 2009, Am J Physiol Endocrinol Metab, 297: E1378-1387; Chung et al., 2008, J Hepatol, 48: 471-478; Chung et al., 2009, Gastroenterology, 136:331-340 e332). Conversely, individuals lacking PEDF because of null mutations have OI type VI, an autosomal recessive form of OI characterized clinically by fractures of bone due to inadequate mineralization (Homan et al., 2011, J. Bone Miner. Res., 26: 2798-2803; Venturi et al., 2012, J Bone Miner Res., 27: 723-728). Bone specimens from patients with OI type VI reveal severely hypomineralized bones that are mirrored in a mouse model of PEDF deficiency (Glorieux et al., 2002, J Bone Miner Res, 17: 30-38; Bogan et al., 2013, J Bone Miner Res., 28: 1531-1536). The mineralization defect was associated with abnormalities in the extracellular matrix that were reported in osteoblast cultures and bones from these mice (Bogan et al., 2013, J Bone Miner Res., 28: 1531-1536). Although exome sequencing established null mutations in the PEDF gene as the cause of OI type VI, a mechanism for the phenotype remains unclear (Becker et al., 2011, Am. J. Hum. Genet., 88: 362-371; Homan et al., 2011, J. Bone Miner. Res., 26: 2798-2803; Venturi et al., 2012, J Bone Miner Res., 27: 723-728).
It has been previously reported that there exists obvious abnormalities of mesenchymal progenitor-derived cells in the livers and pancreas of PEDF knockout (KO) mice (Chung et al., 2009, Gastroenterology, 136:331-340 e332; Schmitz et al., 2011, Am J Pathol, 179: 2990-2999). This included a striking pattern of a-smooth actin staining reflecting activation of mesenchymal progenitor-derived cells (Chung et al., 2009, Gastroenterology, 136:331-340 e332; Schmitz et al., 2011, Am J Pathol, 179: 2990-2999). Also prominent was the marked presence of lipid droplet markers in PEDF KO fibroblasts in organs normally devoid of adipocytes (Grippo et al., 2012, Gut, 61: 1454-146).
A prior study suggested that PEDF may induce osteoblast differentiation from embryonic stem cells, but PEDF dependency was not evaluated (Kang et al., 2009, Stem Cells Dev, 18:77-91). Whether PEDF plays a direct role in the commitment and differentiation of MSCs into adipocytes or osteoblasts, the two cell types underlying the extremes of PEDF-related human diseases, has not been investigated.
Thus, there is a need in the art for compositions and methods for modulating MSC differentiation. The present invention satisfies this unmet need.